A survey of oxidative paracatalytic reactions catalyzed by enzymes that generate carbanionic intermediates: implications for ROS production, cancer etiology, and neurodegenerative diseases.
A survey of oxidative paracatalytic reactions catalyzed by enzymes that generate carbanionic intermediates: implications for ROS production, cancer etiology, and neurodegenerative diseases.
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生成碳负离子中间体的酶催化的氧化副催化反应的调查：对 ROS 产生、癌症病因学和神经退行性疾病的影响。
DOI：
10.1002/9780470920541.ch7
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发表时间：
2011
期刊：
影响因子：
--
通讯作者：
Cooper,ArthurJL
中科院分区：
文献类型：
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作者：
Bunik,VictoriaI;Schloss,JohnV;Pinto,JohnT;Dudareva,Natalia;Cooper,ArthurJL
产生碳负离子中间体的酶通常会催化与 O2 和其他不被视为“正常”反应物的亲电子试剂的副催化反应。例如，含有吡哆醛 5'-磷酸 (PLP) 的猪肾多巴脱羧酶将多巴胺与分子 O2 氧化成 3, 4-二羟基苯乙醛，其催化非氧化性多巴脱羧的速率约为 1%。然而，突变型 Y332F 酶催化多巴化学计量转化为 3, 4-二羟基苯乙醛，这表明即使很小的结构变化也可能改变或引发某些酶催化的副催化反应。几种二磷酸硫胺素 (ThDP) 依赖性酶产生的碳负离子与不同的亲电子试剂发生反应，将一些外源性物质和内源性化合物转化为潜在的生物危险产物。酶和中间体的细胞区隔可能会大大增加副催化反应的有害影响。例如，在参与氧化α-酮酸脱羧的三种多酶复合物中的两种中，第三种组分的副催化反应使第一种碳负离子生成组分失活。在这篇综述中，我们提供了已知催化副催化反应的碳负离子生成酶的概述。我们还讨论了其中一些反应通过疾病引起的代谢状态和/或蛋白质结构的改变而导致癌症和神经变性的不可逆损伤的可能性。
Enzymes that generate carbanionic intermediates often catalyze paracatalytic reactions with O2 and other electrophiles not considered “normal” reactants. For example, pyridoxal 5′-phosphate (PLP)—containing pig kidney dopa decarboxylase oxidizes dopamine with molecular O2 to 3, 4-dihydroxyphenylacetaldehyde at about 1% of the rate at which it catalyzes nonoxidative dopa decarboxylation. The mutant Y332F enzyme, however, catalyzes stoichiometric conversion of dopa to 3, 4-dihydroxyphenylacetaldehyde, suggesting that even minor structural changes may alter or initiate paracatalytic reactions catalyzed by certain enzymes. Carbanions generated by several thiamine diphosphate (ThDP)—dependent enzymes react with different electrophiles, transforming some xenobiotics and endogenous compounds into potentially biologically hazardous products. The detrimental effects of paracatalytic reactions may be greatly increased by cellular compartmentation of enzymes and intermediates. For example, in two of the the three multienzyme complexes involved in oxidative α-keto acid decarboxylation, paracatalytic reactions of the third component inactivate the first carbanion-generating component.In this review we provide an outline of carbanion-generating enzymes known to catalyze paracatalytic reactions. We also discuss the potential of some of these reactions to contribute to irreversible damage in cancer and neurodegeneration through disease-induced alterations in the metabolic state and/or protein structure.